BOSTON—When considering type 2 diabetes, one often thinks of
the synonymous terms of glucose, insulin and pancreas­—but a team of researchers
from Boston Children's Hospital would like the medical research community to
insert a new word into that vernacular: intestine.

In a new study published in the journal Science, a team led by Dr. Nicholas Stylopoulos, a researcher in
Boston Children's Hospital's Division of Endocrinology, offers evidence that
the small intestine—which is often regarded as a "passive" organ—has surprising
involvement in the body's metabolism. Their paradigm-shifting findings could
have tremendous impact on the way patients with type 2 diabetes are treated in
the future.

Stylopoulos' lab is actively engaged in the study of weight
loss surgery in order to discover new biology and achieve a better
understanding of metabolism and weight regulation. Specifically, he and his colleagues
are focused on discovering ways to "reverse engineer" weight loss surgery,
especially Roux-en-Y Gastric Bypass (RYGB), which is currently considered the
most effective treatment option for severe obesity.

"We focus on bariatric surgery because we believe it is the
best treatment for type 2 diabetes," says Stylopoulos. "Our lab focuses on the
mechanism of action in wright loss surgery because we believe we can
reverse-engineer bariatric surgery. That means we want to know the mechanism by
which surgery works and apply this mechanism to create new treatments that
eliminate the need for invasive surgery."

In recent years, as patients who have obesity and type 2
diabetes are increasingly turning to procedures like RYGB, scientists have
documented the link between weight loss surgery and the reversal of type 2
diabetes—although the mechanism of action at play here is not the weight loss
that results from this surgery, as most people may expect. Surprisingly, type 2
diabetes is resolved almost immediately after weight loss surgery–even before
weight loss is achieved.

"Studies about this have been somewhat controversial, but
our understanding of weight loss surgery has changed because clinicians have
noticed that patients who depend on insulin injections and other meds actually
do not require these drugs anymore, even within a week after surgery. This does
not happen with other weight loss procedures and methods," Stylopoulos notes. "Usually,
when you think about the intestine, you don't view it as a glucose-utilizing
organ. The small intestine uses glucose, but not as a main source of fuel. You
do not expect the intestine to assume such an important role and literally
reprogram metabolism."

Before gastric bypass, intestines typically do not contain a
specific transporter called GLUT-1, which is responsible for removing glucose
from circulation and utilizing it within the organ. After gastric bypass, the
researchers found that the intestine reprograms itself to contain GLUT-1,
taking glucose from circulation and disposing of it, swiftly stabilizing blood
glucose levels in the rest of the body.

"GLUT-1 is a glucose transporter, and its job is to put
glucose inside a cell. The intestine expressed Glut only in the fetus. Adults
don't have it. But all of a sudden, after gastric bypass surgery, this
transporter appears again. That is why we talk about reprogramming," explains
Stylopoulos.

To investigate why this happens, Stylopoulos and his team
spent one year studying rats, and observed that after gastric bypass surgery,
the small intestine changes the way it processes glucose. Using positron
emission tomography (PET) scans, the team observed the intestine using and
disposing of glucose, regulating blood glucose levels in the rest of the body
and helping to resolve type 2 diabetes.

"We thought, let's look at the whole animal in a study that
will allow us to look at glucose utilization globally. That is what the PET
scan does. It allows you to visualize glucose utilization. You can take a
picture one hour later and see cells being used. This is very powerful,"
Stylopoulos says.

The team observed that type 2 diabetes was resolved in 100
percent of the rats that underwent gastric bypass surgery. Sixty-four percent
of type 2 diabetes was resolved by the intestine, and the researchers
hypothesize that the other 36 percent may be due to weight loss or other
factors.

These findings pave the way for future investigations of how
to create a medical pathway to mimic the intestine's reprogramming without the
surgery, according to Stylopoulos.

"That is the long-term goal, of course," he says. "You can
imagine treatment based on ways to increase glucose utilization in the
intestine or GLUT-1 transport in the intestine, and a way to force glucose into
the intestine and into cells. In this field, there are a lot of people and
companies trying to find out more about insulin signaling and how we can prove
that, but the fact of the matter is, there are ways of glucose utilization that
are independent of insulin.

Next, Stylopoulos' lab will investigate the same phenomenon
in humans, and further probe how GLUT-1 is regulated in the intestine, which
could potentially be a drugable target.

"Since cells in the intestine have such a short lifespan, we
can easily study and pharmacologically manipulate them to use glucose, without
long-term problems," Stylopoulos points out.

The study, "Reprogramming of Intestinal Glucose Metabolism
and Glycemic Control

in Rats After Gastric Bypass," was published July 26 in Science. Co-lead authors included Drs.
Nima Saeidi, Luca Meoli and Eirini Nestoridi. The research was supported by
funds from Boston Children's Hospital's Department of Medicine and Clinical and
Translational Executive Committee, as well as grants from the U.S. National
Institutes of Health.